Age-related macular degeneration (AMD) is the principal cause of legal blindness in the United States and Western Europe. It affects over 11 million people in this country alone, and with the aging population will exact an even greater toll. The earliest visible abnormality in AMD is the accumulation of drusen (Gass, J. D. (1972) Trans Am Ophthalmol Soc 70, 409-36.), lipoproteinaceous deposits between the retinal pigment epithelium (RPE) and Bruch's membrane, the extracellular matrix between the RPE and the underlying choroid. Drusen are a significant risk factor for progression to choroidal neovascularization (CNV), the principal cause of vision loss in AMD (Macular Photocoagulation Study Group (1997) Arch Ophthalmol 115, 741-7). There is no animal model of drusen resembling that of patients with AMD. Drusen-like deposits in elderly primates (Hope, et al., (1992) Br J Ophthalmol 76, 11-6.) are dissimilar to human drusen both in ultrastructural morphology and biochemical composition (Hirata, A. & Feeney-Burns, L. (1992) Invest Ophthalmol Vis Sci 33, 2079-90; Mullins, R. F. & Hageman, G. S. (1997) in Degenerative Retinal Diseases, ed. LaVail, M. (Plenum Press, New York), pp. 1-10.). Attempts to create a murine model of drusen by high fat diet, disrupting the apolipoprotein E gene, inducing protoporphyria (Gottsch et al., (1993) Arch Ophthalmol 111, 126-9.), accelerating senescence (Majji, et al., (2000) Invest Ophthalmol Vis Sci 41, 3936-42), or combinations of the above (Dithmar et al., (2001) Arch Ophthalmol 119, 1643-9) have not succeeded in creating drusen.
The biogenesis of drusen involves RPE dysfunction, impaired digestion of photoreceptor outer segments, and subsequent debris accumulation (Hageman, et al.,. (2001) Prog Retin Eye Res 20, 705-32). The presence of complement C5, immunoglobulins, apolipoprotein E, vitronectin, and clusterin in human drusen (Loffler, et al., (1986) Graefes Arch Clin Exp Ophthalmol 224, 493-501; Hageman, G. S., et al., (1999) FASEB J 13, 477-84; Hageman, G. S. & Mullins, R. F. (1999) Mol Vis 5, 28; Johnson, et al., (2000) Exp Eye Res 70, 441-9; Mullins et al., (2000) FASEB J 14, 835-46; and Anderson, et al., (2001) Am J Ophthalmol 131, 767-81) suggests that focal concentration of these materials may produce a powerful chemotactic stimulus for leukocytes, possibly acting via a complement cascade (Killingsworth, et al., (2001) Exp Eye Res 73, 887-96). Consistent with this, macrophages appear to preferentially engulf the wide-banded collagen of basal deposits in patients with AMD, suggesting a role in drusen clearance (Loffler, K. U. & Lee, W. R. (1986) Graefes Arch Clin Exp Ophthalmol 224, 493-501; Killingsworth, et al., (1990) Eye 4, 613-21; Penfold, P. L., et al., (1985) Graefes Arch Clin Exp Ophthalmol 223, 69-76; and van der Schaft, et al., (1993) Br J Ophthalmol 77, 657-61). Laser photocoagulation induced regression of drusen in humans (Ho, et al., (1999) Ophthalmology 106, 1367-73; and Olk, et al., (1999) Ophthalmology 106, 2082-90) is believed to result from recruitment of macrophages that resorb these deposits (Duvall, J. & Tso, M. O. (1985) Arch Ophthalmol 103, 694-703).
The lack of a faithful animal model of AMD has hampered both the study and treatment of age-related macular degeneration. Thus, there is a need for a faithful animal model of drusen development and accumulation to provide mechanistic insights into the development of AMD and assist in evaluating candidate drugs for the treatment of age-related macular degeneration.